Vitamin D Deficiency in Saudi Patients With Rheumatoid Arthritis

Background Epidemiological studies indicate that vitamin D deficiency may increase the risk of developing autoimmune and chronic diseases such as rheumatoid arthritis (RA) and, therefore, is prevalent in patients with RA. Additionally, vitamin D insufficiency is associated with significant disease activity in patients with RA. This study aimed to assess the prevalence of vitamin D deficiency in Saudi patients with RA and determine whether there is an association between low vitamin D levels and RA disease activity. Methodology This cross-sectional retrospective study was conducted from October 2022 to November 2022 on patients who attended the rheumatology clinic at King Salman bin Abdulaziz Medical City, Medina, Saudi Arabia. Patients aged ≥18 years, diagnosed with RA, and not on vitamin D supplements were included. Demographic, clinical, and laboratory data were collected. Disease activity was measured using the disease activity score index of a 28-joint count using the erythrocyte sedimentation rate (DAS28-ESR). Results In total, 103 patients were included, with 79 patients being women (76.7%) and 24 being men (23.3%). The vitamin D level ranged from 5.13 to 94 ng/mL, with a median of 24. Of the studied cases, 42.7% had insufficient vitamin D levels, 22.3% had a deficiency, and 15.5% had severe deficiency. There were statistically significant correlations between the median vitamin D level and C-reactive protein (CRP), the number of swollen joints, and DAS. A lower median vitamin D level was detected among cases with positive CRP, swollen joints >5, and higher disease activity. Conclusions Patients with RA in Saudi Arabia were more likely to have low vitamin D levels. Moreover, vitamin D deficiency was linked to disease activity. Therefore, the measurement of vitamin D levels in patients with RA is essential, and vitamin D supplements might be important to improve disease outcomes and prognoses.


Introduction
Vitamin D plays a role in maintaining a healthy mineralized skeleton by influencing the metabolism of calcium and phosphate [1]. Vitamin D is a secosteroid, a compound similar to a steroid but without two of the four carbon atoms in the steroid B ring [2,3]. In recent years, cells in the immune system have been found to contain the vitamin D receptor (VDR), and the fact that several of these cells release vitamin D has raised the possibility of its immunoregulatory qualities [4]. In addition, in the 1980s, researchers noticed that some tissues, other than the kidneys, can produce the active form of vitamin D, which is not regulated by parathyroid hormone (PTH), and identified high-VDR expression in these tissues [5]. The active form of vitamin D modulates the immune system and reduces the activation of the acquired immune system [6]. Vitamin D deficiency has been associated with altered cellular functions and increased risk of inflammatory diseases, such as rheumatoid arthritis (RA) [7]. Several studies have found a relationship between vitamin D deficiency and autoimmune diseases, such as type 1 diabetes mellitus (T1DM) [8], multiple sclerosis (MS) [9], systemic lupus erythematosus (SLE) [10], and RA [11]. However, whether vitamin D deficiency is associated with the pathogenesis of autoimmune diseases or affects the severity and progression of the disease remains unclear [12]. Vitamin D deficiency is common in patients with RA and is associated with disease activity [13,14]. In addition, according to RA-related studies, vitamin D could be a potential therapeutic biomarker and can be used to monitor disease progression as well as treatment efficacy in patients with RA [15].
This study investigated the prevalence of low-serum vitamin D levels in Saudi patients with RA and determined the impact of low-serum vitamin D levels on RA disease activity.

Study design and study population
A cross-sectional study was conducted using medical records of patients with RA who visited the rheumatology clinic at King Salman bin Abdulaziz Medical City, Medina, Saudi Arabia, from October 2022 to November 2022. The inclusion criteria were patients aged 18 years or older who were diagnosed with RA. The diagnosis was made according to the 2010 RA classification criteria. Patients younger than 18 years of age and on vitamin D supplements were excluded. In total, 103 patients were included in this study.

Data collection
The following data were collected: sociodemographic information (age and sex) and disease-related variables, including disease duration, 28-item tender joint count (TJC28), 28-item swollen joint count (SJC28), and RA-specific treatment, including glucocorticoids, disease-modifying antirheumatic drugs, and biologic therapy. Baseline laboratory investigations to monitor the RA profile as part of routine follow-up care for the patient, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), were also documented. The rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) status were also documented. Serum vitamin D levels were measured using 25-hydroxyvitamin D (25(OH)D) total commercial radioimmunoassay in a single laboratory. Vitamin D insufficiency, deficiency, and severe deficiency were defined as a serum level of 20-30, <20, and <12 ng/mL, respectively.
Disease activity was defined based on the disease activity score index of a 28-joint count (DAS28) using the ESR. Patients were categorized into groups according to DAS28: remission (<2.6), low disease activity (2.6-3.2), medium disease activity (3.2-5.1), and high disease activity (>5.1).

Ethical and administrative considerations
Ethical approval was obtained from the Scientific Research Ethics Committee of the College of Medicine, Taibah University, project ID TU-004-22. All the enrolled subjects signed a consent form before participating in the study.

Statistical analysis
Data analysis was performed using SPSS version 22 (IBM Corp., Armonk, NY, USA), with qualitative data presented as numbers and percentages. Quantitative data tested for normality by the Kolmogorov-Smirnov test were described as mean and standard deviation for normally distributed data as well as median and range for nonnormally distributed data. The appropriate statistical test was applied according to data type: chi-square test for categorical variables, student's t-test for continuous variables, and Pearson and Spearman correlation to correlate continuous variables.

Results
This study included 103 Saudi patients with RA, with a mean age (± standard deviation, or SD) of 51.06 ± 15.58 years, comprising 79 women (76.7%) and 24 men (23.3%). Disease duration (measured in years) was 1 to 5, 5 to ≤10, >10, and less than one year in 60.2%, 25.2%, 9.7%, and 4.9% of patients, respectively. RF was positive in 63.1%, and anti-CCP was positive in 40.9%. The baseline characteristics of the patients are summarized in Table 1.  Regarding RA medications, 65%, 61.2%, and 57.3% of the patients were on methotrexate, hydroxychloroquine, and prednisone, respectively, at the time of vitamin D measurement, as shown in Table  2.   ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; TJC, tender joint count; SJC, swollen joint count; DAS28, disease activity score 28 The median vitamin D level was 24 (range 5.13-94). Of the studied cases, 42.7% were vitamin D insufficient, while 22.3% and 15.5% of the patients had vitamin D deficiency and severe deficiency, respectively, as shown in Table 4.

MC, Monte Carlo; NSAID, nonsteroidal anti-inflammatory drug
Statistically significant correlations between median vitamin D level and CRP, number of swollen joints, and DAS28 were observed. Lower median vitamin D was detected in patients with positive CRP, more than five swollen joints, and higher disease activity by DAS28 ( Table 6).

Vitamin D, median (range)
Test of significance  In addition, a statistically significant negative correlation between vitamin D and ESR levels as well as DAS28 was detected, as shown in Table 7, Figure 1, and Figure 2.

Discussion
RA is a chronic inflammatory and autoimmune disease that causes synovitis of the peripheral joints and extra-articular symptoms. Uncontrolled inflammation can lead to joint damage, loss of function, and disability if left untreated. RA is caused by both genetic and nongenetic factors, such as hormonal, environmental, and infectious factors. Vitamin D could be an environmental factor, and immunological research has indicated that many chronic and immune disorders are caused by vitamin D deficiency [13,16]. It has been shown that vitamin D affects the innate and adaptive immune systems primarily via toll-like receptors (TLRs) and differentiation of T-cells, predominately Th17 cells, which play an essential role in the pathogenesis of RA [17].
Vitamin D deficiency is common in patients with RA, with a prevalence estimated to range from 30% to 63% [18]. Our study found that low vitamin D levels were common in patients with RA, among which, 42.7% were vitamin D-insufficient, while 22.3% and 15.5% had vitamin D deficiency and severe deficiency, respectively. Several studies have shown that patients with RA commonly have low vitamin D levels. In a previous study conducted in Italy, 1,191 consecutive patients with RA (85% were women) from 22 Italian rheumatology facilities and 1,019 controls who did not take vitamin D supplements were compared. The results showed that 55% of the patients with RA did not use vitamin D supplements and 52% of them had vitamin D deficiency (25(OH)D levels <20 ng/mL), which is slightly higher than our findings [18]. Another Saudi cross-sectional study included a sample of 102 patients with RA, aged between 22 and 75 years, from a population of 239 patients with RA of both genders. In the study sample, vitamin D deficiency was found in 59 patients (57.8%; 25(OH)D value 20 ng/mL), which is higher when compared to our study's results. Furthermore, vitamin D insufficiency was found in 32 patients (31.4%; 25(OH)D 20-30 ng/mL) [19], which is lower compared to our results.
Although most previous studies have reported similar findings, some case-control studies failed to find differences in vitamin D status between patients with RA and controls [20,21].
In our study, we also observed a positive association between low vitamin D levels and disease activity in patients with RA. An inverse relationship between vitamin D levels and disease activity has been reported in several previous studies [13,14,16,18]. Similar findings were obtained in Saudi Arabia, where there was a significant negative correlation between vitamin D and disease activity in patients [2,19,22]. Although most previous studies observed an inverse correlation between vitamin D deficiency and RA disease activity, some studies did not show a strong association between vitamin D level and RA disease activity [20,23,24]. Blaney et al. presumed that vitamin D could be used as a clinical biomarker for RA and other autoimmune diseases [25]. A previous Saudi study found that low vitamin D levels in patients with RA could be a reliable indicator of high disease activity. Low vitamin D has been defined as a level less than 12.3 ng/mL [19]. Additionally, it has been shown that vitamin D intake negatively correlates with RA [26].

Limitations
The limitations of this study include its single center and small sample size, as well as its design, which includes the drawbacks common to cross-sectional studies, such as an unknowable temporal sequence of linked factors. The lack of a control group is also a limitation. Furthermore, confounding variables such as sun exposure, food habits, and nutritional status must be considered. Further prospective, multicenter, and large-sample-size studies are required.

Conclusions
Our results show that vitamin D deficiency was common in Saudi patients with RA. Additionally, vitamin D deficiency was correlated with RA disease activity. Therefore, the measurement of vitamin D levels in patients with RA is essential, and vitamin D supplements might be important to improve disease outcomes and prognoses. Further prospective trials are required to assess the efficacy of vitamin D supplementation in the treatment and amelioration of RA symptoms and inflammatory responses. Additionally, the optimal vitamin D dose and intervention duration must also be determined.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. The Scientific Research Ethics Committee of College of Medicine, Taibah University issued approval Project ID TU-004-22. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.